The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis.

Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2 bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis.

LAT1 enables T cell activation under inflammatory conditions.

The aim of this study was to assess the L-type amino acid transporter-1 (LAT1) as a possible therapeutic target for rheumatoid arthritis (RA). Synovial LAT1 expression in RA was monitored by immunohistochemistry and transcriptomic datasets. The contribution of LAT1 to gene expression and immune synapse formation was assessed by RNA-sequencing and total internal reflection fluorescent (TIRF) microscopy, respectively.

Novel Synthesis of C-Methylated Phytocannabinoids Bearing Anti-inflammatory Properties.

There is growing interest in non-psychoactive phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), and cannabichromene, as potential leads for novel therapeutic agents. In this study, we report on the development of new derivatives in which we methylated either position 4 of olivetol or the phenolic positions of olivetol, or both. We introduce a refinement on previously reported chemical procedures for phytocannabinoid derivatization as well as the biological evaluation of all derivatives in anti-inflammatory in vivo models.

Modulation of immune cell function, IDO expression and kynurenine production by the quorum sensor 2-heptyl-3-hydroxy-4-quinolone (PQS).

Many invasive micro-organisms produce 'quorum sensor' molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS to mice with collagen-induced arthritis (CIA) increased the severity of disease.

Standardization of Antigen-Emulsion Preparations for the Induction of Autoimmune Disease Models.

Autoimmune murine disease models are vital tools for identifying novel targets and finding better treatments for human diseases. Complete Freund's adjuvant is commonly used to induce disease in autoimmune models, and the quality of the adjuvant/autoantigen emulsion is of critical importance in determining reproducibility. We have established an emulsification method using a standard homogenizer and specially designed receptacle.

Novel CBG Derivatives Can Reduce Inflammation, Pain and Obesity.

Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and show them to possess anti-inflammatory and analgesic properties. In addition, unlike CBG, HUM-234 also prevents obesity in mice fed a high-fat diet (HFD).

Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis.

Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity.

Early detection of osteoarthritis in the rat with an antibody specific to type II collagen modified by reactive oxygen species.

Background: Osteoarthritis (OA) is a disease of the whole joint, with articular cartilage breakdown as a major characteristic. Inflammatory mediators, proteases, and oxidants produced by chondrocytes are known to be responsible for driving cartilage degradation. Nevertheless, the early pathogenic events are still unclear.

Targeting Extracellular Vesicles to the Arthritic Joint Using a Damaged Cartilage-Specific Antibody.

The targeted delivery of therapies to diseased tissues offers a safe opportunity to achieve optimal efficacy while limiting systemic exposure. These considerations apply to many disease indications but are especially relevant for rheumatoid arthritis (RA), as RA is a systemic autoimmune disease which affects multiple joints. We have identified an antibody that is specific to damaged arthritic cartilage (anti-ROS-CII) that can be used to deliver treatments specifically to arthritic joints, yielding augmented efficacy in experimental arthritis.

IDO activation, inflammation and musculoskeletal disease.

The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age.